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With particular thanks to Dr James Isbister of Sydney, Australia
2
John FreedmanDirector, Transfusion Medicine
St Michael’s HospitalUniversity of Toronto
Blood Transfusion: An expensive & potentially hazardous alternative to
Blood Management
3
I won’t keep you long
As Henry VIII said to each of his 6 wives
4
Objectives of this presentationTo gain an understanding of:
Risks of allogeneic transfusion Infectious Immunologic (TRALI, immunomodulation) Errors
Blood conservation/transfusion alternatives
An Ontario approach to blood conservation
5
Blood will immerse you in a world of horror unlike any you've experienced before. Brace yourself for a nightmarish battle against the bloodthirsty minions of an ancient, forgotten god bent on wiping humanity from the face of the earth
With thanks toDr James Isbister, Sydney, SABM 2005
6
כי נפש הבשר בדם הוא
Leviticus 17 ויקרא (‘the life/soul of the flesh is in the blood’)
1:18,000 units to wrong pt
Blood transfusion: other than as a scarce and expensive resource, who cares?
7
Blood transfusion Patients think blood transfusion is
special and beneficial, but have difficulty accepting small risks they can’t control.
Blood Donors believe their contribution is a gift to the community that will be used appropriately and safely
Clinicians think blood is ordinary, take blood transfusion for granted, benefit is assumed and risks regarded as minimal.
Governments view blood as a commodity and transfusion medicine as an expensive support service which should be regulated and funded in a cost-effective manner.
8
9
• 1997 Krever Commission: Recommendation #9:
“It is recommended that ….. promote appropriate use of, and alternatives to, blood components and blood products.”
• 1996 Gallup Poll indicates that only 7% of respondents would want to receive donated blood; 82% think patients should have the right to make final decision
10
Residual risk
HIV 1:10 million
HCV 1:3 million
HBV 1:72,000 (no NAT)
HTLV 1:1.1 million
Virus TTI
Per unit
MVA 1: 9,000
Home accident 1: 10,000
Murdered in Canada 1: 85,000
General anaesthesia 1: 20-50,000
Lightning 1: 3,000,000
Risk of death from:
(actuarial tables)
Chiavetta et al, CMAJ, 169:67-73, 2003
11
Standard collection pouchStandard collection pouch
Skin fragment
Bacterial contamination
bacterialcontamination
bacterialcontamination
bacterial survival in component
bacterial survival in component
febrilereactionfebrile
reactionsevere
reactionsevere
reactionfatalityfatality
103103102102104104
105105106106
0
2
4
6
8
10
12
1 2 3 4 5
Days of storage
Lo
g C
FU
/ml
12
Bacterial contamination of platelets
N plt type % positive
Blajchman (1995) 15,838 RDP 0.04%
Risk of receiving BCP 50-250-fold > combined risk from virus TTI.
Estimated that BCP kill ≈15 Canadians/yr
14
vCJD (variant Creutzfeldt-Jakob)
First case in UK in 1996; annual increase; ? peaked
167 cases of vCJD worldwide; 1 in Canada
Human cases about 5 yrs after BSE epidemic
Growth hormone, corneas, ---
?No transfusion-transmitted cases
Currently no screening test for vCJD
Geographic exclusion criteria for donor exclusionLlewelyn et al: Lancet 363:417-421, 2004
Peden et al: Lancet 364:527-529, 2004
1994 2003
15
TRALI: Transfusion-related acute lung injury
leading cause of transfusion-related death
Anti-leukocyte antibody, usually in the donor blood product
16
TRALI cases: Canada
• Age – median 68 years, range 16-94 years
• Sex – female 45%, male 55%
• Blood pressure – 30% hypotension, 24% hypertension,
• 75% perioperative (CVS), haem/onc, trauma patients
TRALI cases per year
1998
-200
020
0120
0220
0320
0420
050
10
20
30
40
50
60
70
80
Nu
mb
er
of
ca
se
s
17
New acute lung injury; bilateral pulmonary infiltrates
• Within 6 hours of plasma-containing transfusion
• Acute respiratory distress
TRALI:
• Fever (1 to 2 oC)
• No evidence of circulatory overload
. ● HypoxemiaPaO2 of 30 – 50 torr;
PaO2/FIO2 <300 mm Hg;
O2 saturation < 90% on room air
18
TRALI:often difficult to know if X-ray image that of noncardiogenic pulmonary edema
• Rales and diminished breath sounds
• Normal jugular venous pressure
• Normal/low pulmonary wedge pressure
• Does not respond to diuretics
• Hypotension does not respond to intravenous fluids
• Absent S3
19
TRALI patients
• 17% died
• 48% mechanical ventilation (70% of those who died)
• Donor α-leukocyte antibodies in 63%
α-PMN in 54% of those who died vs in 25% of patients who recovered;
sicker patients also frequently received components containing α-HLA,
particularly class II
20
Donors • Overall, 18 % of donors had anti-HLA
(29% female vs 7% male)
• 9 % of donors had anti-PMN (equal frequency female & male)
• ?? Remove suspect donors from the donor pool;
• ?? Remove female blood donors
• Many donors implicated had donated many times before (in one case >200 times) without a previously reported TRALI reaction
Frequency of antibodies in donors
-HLA
clas
s I
clas
s II
clas
s I +
II
-PM
N
0
5
10
15
20
25
30 FemalesMales
perc
ent
21
Donor blood products with α-leukocyte antibodies implicated in TRALI cases
Product transfused Percentage
Packed red blood cells 31 %
Random donor platelets 29 %
Fresh frozen plasma 18 %
Whole blood 4 %
Apheresis platelets 3 %
Cryosupernatant plasma 1 %
Cryoprecipitate 1 %
Not reported 13 %
22
Capillary leak syndrome
Pulmonary damage
Pulmonary endothelial damage
Susceptible patient• Sepsis• Surgery (CPB)• Trauma
Transfusion:BRMs:• Lipids (Lyso-PCs)• Cytokines• Antibodies
Activation of EC
chemokines
PMN primed
primed PMN sequester on EC, adhere, cytoskeletal change, rigid, trapped in microvasculature
Hyper-reactive PMN
Release enzymes
1 2
TRALI
adhesion molecules
Antibody to WBC
Ag/Ab reaction
C’ activation
Leukosequestration
Silliman et al: Non-immunogenic TRALI. 2 stage process.
i. Susceptible patient: sepsis, surgery, trauma,
ii. Transfusion
Immunogenic TRALI: Classical theory, anti-leukocyte antibody, but antibody not always found.
Pulmonary endothelium
23
1 Susceptible pt: sepsis, surgery, trauma
Activated EC ChemokinesAdhesion molecules on EC
2 Transfusion (BRM)Lipids (lyso-PCs)
Cytokines
(antibodies, microvesicles, cell fragments)
O2-
Attraction Tethering
Capillary leak
Lung damageTRALI
Pulmonary endothelium
Primed PMN
Rigid
Trapped . in mv
Hyper-reactive
enzymes
Firm Adhesion Activation EC damage
24
Transfusion-induced immunomodulation
Renal allograft survival [Opelz & Terasaki, 1981]
Graft one year survival rates
23% in patients not transfused
87% in patients receiving > 10 transfusions
transfusion-induced immunosuppression (allogeneic leukocytes)
25
Transfusion-induced immunomodulation(due to allogeneic leukocytes)
Some potential mechanisms:
• Clonal deletion or anergy (of CTLs)
• Induction of suppressor cells
• Production of antiidiotypic antibody
• Suppression of NK cell activity
• Polarization of cytokine response
26
10/16 observational studies and 4/5 randomized trials showed statistically significant reduction in postoperative infections with autologous versus allogeneic transfusions.
Infections & perioperative transfusion
Even more true for no transfusion versus allogeneic transfusion
27
In various surgical settings, no variable was moreconsistently associated with postoperative infection
than was perioperative allogeneic transfusion
For each allogeneic RBC unit given, 1.5 fold increase in nosocomial infection.
Translates into potential morbidity, mortality and LOS.
(Koval et al, J Orthop Trauma, 1997, 11:260)
28
IBCT (213) 67.6%
ATR (37) 11.7%
DTR (40) 12.7%
TTI (6) 1.9%
PTP (3) 1.0%
TRALI (15) 4.8%
TA-GVHD (1) 0.3%
SHOT, UK, annual report 2000-01Adverse effects of transfusion
Incorrect blood component transfused (IBCT): “Wrong blood” is, without exception, an
avoidable error
IBCT 67.6%Acute HTR 11.7%
Delayed HTR 12.7%
TTI 1.9%TRALI 4.8%
PTP 1.0%TA-GvHD 0.3%
29
SHOT 1996/97 to 2001/01
• Blood centre 2%
• Transfusion laboratory 28%
• Collection, administration 55%
• Prescription, sampling, request 13%
• Other 1%
• Unknown <1%
.
68% Wards
30
CBS Projections: Collections vs Demands
31
Cost of Blood Transfusion (in US$, 1998)
• Overhead = facility cost• Variable direct labour = lab technologists,
phlebotomists, nurses
• Fixed direct labour = administrators, etc.• Direct material = supplies, blood, tests
.
Cremieux P-Y, Barrett B, Anderson K, Slavin MB. J Clin Oncol 18:2755, 2000
Fixed DirectLabour 18%
Overhead46%
Variable Direct Labour 17%
Direct Material
19%
Mean Overall Cost: $491-$545 per unit.
Ontario blood budget: $420 million per year
32
Costs incurred in provision of blood
• Recruitment and collections
• Infectious disease testing
• Manufacturing, shipping, handling, labelling
• Pre-transfusion testing
• Transfusion costs
• Post-transfusion sequelae
• Regulatory and legal costs
33
Hospital charges• Blood type ABO $ 156• Blood type Rh 85• Antibody screen 182• Crossmatch, immediate spin 350• Crossmatch, antiglobulin (Coombs) 391• Red cell antigen screening, per antigen 108• Fresh frozen plasma thawing 156• Crypoprecipitate pooling 43• Handling 86• Surcharge 15%
Zeger, Jabbour (USC): Transfusion-free medicine and surgery, 2005, Blackwell
34
COSTS: Adult open heart surgeryProduct Number Product
fee/unit ($)
Hospital fee/unit ($)
Total ($)
Red cells 6 276 477 4520
FFP 5 53 250 1515
Platelets 1 500 200 1400
ABO type 1 156 185
Rh type 1 85 85
Antibody screen
1 182 182
Total $ 7,887
Jabbour, 2005
35
It is clear that:
1) the demand for blood outweighs the supply
2) there are real risks associated with blood transfusion
3) blood is not ‘free’
36
Blood transfusion is a lot like marriage. It should not be entered into lightly,
unadvisedly or wantonly,or more often
than is absolutely necessary.
[Beal RW: Aust N Z J Surg 46:309, 1976]
37
Blood is Good?????
38
1960
1971
39
EnoughEnough In the right placeIn the right place At the right timeAt the right time And not too muchAnd not too much
Most people in this room will depart Most people in this room will depart Earth as a result of not maintaining Earth as a result of not maintaining one or more of these functions of the one or more of these functions of the bloodblood
Blood
J Isbister, SABM 2005
40
41
• Allogeneic transfusion avoidance
• Transfusion reduction
Blood Conservation: AimsManagement
42
Goals: Minimize Anemia and Avoid Allogeneic Blood Transfusion.
Anemia(Reduced
Hematocrit)
Allogeneic Transfusion
Risk
Transfusion has risks,but bleeding to death is fatal !
43
In the ICU, most patients anemic at time of admission.
Hb typically declines by at least 0.5 g/dL/day in first 3 d of ICU stay. Continues to decline if sepsis/severe illness.
These patients particularly may be at risk from anemia (cardiovascular, respiratory, metabolic compromise).
Etiology of anemia multifactorial:phlebotomy, GI bleeding, coagulopathy, blood loss from vascular procedures, renal failure, nutritional deficiencies, marrow suppression, impaired erythropoietin response, etc
Anemia is common: 30% patients preop
44
“I need you to find a radically innovative new way to keep
everything exactly the same”
Office of the Director of Medical
Services
BloodConservation?
?
45
Blood conservation approaches in surgery
Autologous blood (PAD, cell salvage, ANH) Erythropoietin (EPO, Eprex) Other pharmacologics (e.g. antifibrinolytics) Fibrin glues (e.g. Tisseel) Hemostatic/harmonic scalpels Blood substitutes Controlled hypotension; positioning Minimally invasive surgery Transfusion trigger (level of Hb) rFVIIa
etc
46
Preoperative Autologous Donation (PAD) in primary hip surgery:
No PAD, 29% had allogeneic transfusionPAD, 6% had allogeneic transfusion
(B Feagan; 2001/2002); 28 Ontario sites; 3352 pts
Is blood conservation approach effective in avoiding allogeneic transfusion?
47
Pre-operative EPO for Orthopaedic SurgeryFeagan BG et al. Ann Intern Med 133:845-854, 2000.
Allogeneic Blood Transfusions 45% in placebo group 23% in low dose EPO (p<0.003) 11% in high dose EPO (p< 0.001)
Significant requirement for supplemental iron Monitor serum ferritin, transferrin saturation
48
Hb pre-op % transfused< 130 53 %> 130 20 %
But, ifHb done in PAF < 130 > 130
Initial Hb level predictive of transfusion.
EPOIronB12, folate
BC Capital Health Region
15%
5%
49
Operative mortality increases with untreated anemia.Preop Hb Mortality
< 60 g/L 62%
61 - 80 33%
81 - 100 0%
> 100 7%
Carson, Am J Surg 170:6A:32S, 1995
Adjusting for APACHE II score: Post-op, 2.5X increase in odds of death for each 10 g/L decrease in Hb below 80 g/L
Transfusion trigger: How much Hb do you need?
(Carson et al: Transfusion 42:812, 2002)
50
.
Crude in-hospital survival rate of patients with different preoperative haemoglobin concentrations
.Lancet, Vol 369, May 18, 2002
Preoperative haemoglobin >100g/L
Preoperative haemoglobin ≤100g/L
.
So level of Hgb important, but at what trigger should one transfuse?
51
So how many red cells do you need?
“The bad news is, you have only one red blood cell.The good news is, he’s a workaholic!”
52
Hébert et al; NEJM 340:409, 1999: ICU patients (TRICC)
Transfusion trigger randomized by Hb (70 vs 100 g/L)restrictive liberal
Units transfused 2.6 5.4
Mean Hb values 85 107
Hospital morbidity 22% 28%
ICU mortality 14% 16%
30 day mortality 19% 23%
Organ failure score 8.3 8.8
Trend to improved survival in restricted group (p=0.10)
53
1940’s – 80’s: Hb 100g/L
1980’s – 2005: Hb 80g/L70g/L60g/L70g/L
Transfusion Transfusion triggertrigger
54
WHAT HGB LEVEL?WHAT HGB LEVEL?
• SAFE PREOPERATIVE SAFE PREOPERATIVE HGB WILL VARY FROM HGB WILL VARY FROM ONE PATIENT TO THE ONE PATIENT TO THE NEXT, NEXT, ANDAND
• SAFE PREOPERATIVE SAFE PREOPERATIVE HGB WILL VARY FOR HGB WILL VARY FOR THE THE SAMESAME PATIENT PATIENT DEPENDING ON DEPENDING ON CLINICAL CLINICAL CIRCUMSTANCESCIRCUMSTANCES
55
When Does Anemic Organ Injury Occur?
70 g.L-1 100 g.L-1
Hemoglobin Concentration
30 g.L-1 90 g.L-1
Clinical Evidence Of Harm
Tissue Hypoxia
Activation of Protective Mechanisms
56
What is the Optimal Transfusion Threshold ?
70 g.L-1 100 g.L-1
Hemoglobin Concentration
30 g.L-1 90 g.L-1
No Co-Morbidities
Co-Morbidities
????
AnaerobicMetabolism
57
Adjusted odds ratio for mortality according to preoperative hemoglobin concentration in patients refusing red blood cell (RBC) transfusions.
While cardiovascular disease (CVD) increases the risk of mortality, increased blood loss during surgery (resulting in a decrease in Hb) are also associated with an important rise in the risk of death.
Adapted from Carson JL et al. Lancet 348: 1055, 1996.
.
.
.
Hb decrease 2 – 3.9 g/dLHb decrease > 4 g/dL
Hb decrease 2-3.9 g/dL + CVD
58
Blood ManagementBlood Managementis all aboutis all about
OxygenOxygen HemostasisHemostasis
59
J Isbister, SABM 2005
Tour de France
Arsenal FC
Modified from James Isbister, SABM 2005
60
ATPATPCO2
O2
HbO2
HbO2
Hemoglobin
Hemoglobin
O2
HbO2
O2
MyoglobinO2
O2
O2
Co
nsu
mp
tio
nO2 Delivery DO2
Inspired PO2
Lung Fn (Diffusion)
Red Cell& Hb Function Cardiac &
Vascular Fn Red Cell, HbEndothelial Fn Interstitial
Space
TissueMetabolism
With thanks to James Isbister, SABM 2005 (modified)
61
Limit transfusion to appropriate need. Transfuse unit by unit.There is no single Hb value optimal for all patients:
consider factors such as:Cardiac output
Heart rate, stroke volume, contractilityPeripheral vascular resistance
Increased O2 release from red cellDecreased blood viscosity
Dilution
Assessing Efficacy• Red cell survival• Hemoglobin level• Patient symptoms• Doctor feels better
62
DEVELOPING A NETWORK of ONTARIO TRANSFUSION COORDINATORS
Enhance transfusion practice outside of the Blood Bank* ‘clinical bridge’ between Transfusion Service & rest of hospital
Interact with physicians, nurses & patients to promote . blood conservation & alternatives to allogeneic transfusion
Anticipated a 5 to 10% reduction in red cell use
.
MOH
Susan Gagne; Niagara Health System; 905-684-7271 ext 46570
63
Pre-operative approach
assess at pre-admission clinic (3-5 weeks before surgery)
identify patients at risk of transfusion ahead of surgery
discuss informed consent and transfusion alternatives
investigate, diagnose and treat anemia
(family doctor, surgeon, anesthetist, hematologist)
erythropoietin and / or iron
predonation of autologous blood (with hematinics + EPO)
stop anticoagulants/antiplatelet drugs if safe to do so
minimize blood taken for lab testing
64
Progress
• At specific time periods, collect detailed anonymized patient information for a defined number of all consecutive patients admitted for the designated procedures
• Evaluations: Baseline (Jan 2002), 12, 18 & 24 months
• Aggregate data for Ministry of Health of Ontario; Site-specific
data for each institution
[Guelph General Hospital, Hamilton Health Sciences Centre, Hospital for Sick Children (Toronto), Kingston General Hospital, Lakeridge Health (Oshawa), London Health Science Centre, Mt Sinai Hospital (Toronto), Niagara Health System, North Bay General Hospital, Peterborough Regional Health Centre, Sault Area Hospitals (Sault St Marie), Scarborough General Hospital, St Joseph’s Health Centre (Toronto), St Mary’s General Hospital (Kitchener), St Michael’s Hospital (Toronto), Sudbury Regional Hospital, Sunnybrook & Women’s College Health Sciences Centre (Toronto), The Ottawa Hospital, Toronto East General Hospital, Trillium Health Centre (Mississauga), University Health Network (Toronto), Windsor Regional Hospital]
10
10
HSC, MSH, UHN, TEGH, SJH, SWCHC, SMH, BrH, Tr,
23 hospitals chosen based on blood utilization & geography
65
0
20
40
60
80
100
Per
cen
tag
e o
f ho
spita
ls
White = pre-ONTraCBlue = at 6 mosYellow = at 16 mosRed = at 24 mos
Education in-services in previous 6 mos:Pre-Ontrac = < 20At 6 mos = > 140At 16 mos = > 250At 24 mos = > 290
66
Knee arthroplasty:
19 hospitals; 1150 patients at each time point
AAA surgery:
17 hospitals; 300 patients at each time point
CABG surgery (primary):
4 hospitals; 300 patients at each time point
Three targeted surgical procedures
674
Proportion of knee surgery patients (N=1119)who received allogeneic blood
ALL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 230
10
20
30
40
50
60
70
80
90
100
X X X X
Site number
Pe
rcen
t tr
an
sfu
sed
one knee
Revisionknees
Bilateralknees
BASELINE
At baseline, marked variation across province in likelihood of receiving a transfusion 4
Mean for:
Aggr
685
One Knee: % With Allogeneic Transfusion Baseline vs 12 Months, by site
0
20
40
60
80
100
All 1 2 3 4 5 6 8 9 10 11 12 14 15 16 17 18 19 20 21 22
Site Number
% A
l l o
g e
n e
i c
AAAs: % With Allogeneic Transfusion (Baseline vs 12 Months) by site
0102030405060708090
100
2 3 4 7 8 9 10 11 12 14 15 16 17 18 19 21 22 23
Site Number
% A
llo
Baseline
12 Month
CABGs: % With Allogeneic Transfusion
0
20
40
60
80
100
All 4 7 18 23
Site Number
% A
lloge
neic Baseline
12 Month
All
All
Blue baselineRed 12 months
urgent
elective
At 12 months, most, but not all, hospitals showed a reduction in the proportion of patients transfused with allogeneic RCC
Baseline vs 12 months; % receiving allogeneic transfusion
One knee
AAA CABG
5
695
One Knee: % With Allogeneic Transfusion Baseline vs 12 Months, by site
0
20
40
60
80
100
All 1 2 3 4 5 6 8 9 10 11 12 14 15 16 17 18 19 20 21 22
Site Number
% A
l l o
g e
n e
i c
AAAs: % With Allogeneic Transfusion (Baseline vs 12 Months) by site
0102030405060708090
100
2 3 4 7 8 9 10 11 12 14 15 16 17 18 19 21 22 23
Site Number
% A
llo
Baseline
12 Month
CABGs: % With Allogeneic Transfusion
0
20
40
60
80
100
All 4 7 18 23
Site Number
% A
lloge
neic Baseline
12 Month
All
All
Blue baselineRed 12 months
urgent
elective
At 12 months, most, but not all, hospitals showed a reduction in the proportion of patients transfused with allogeneic RCC
Baseline vs 12 months; % receiving allogeneic transfusion
One knee
AAA CABG
5
70
Percent transfused with allogeneic RCC
05
10
1520
2530
354045
5055
60baseline
12 mos
18 mos
24 mos
pe
rce
nt
Non-autologous pts Autologous pts
71
10
knee CABG AAA0
10
20
30
40
per
cen
t re
du
ctio
nProjected % reduction from baseline in allogeneicRCC use for province for the 3 targeted procedures
At 12 mos
At 18 mos RCC use 2003 vs 2002
Ontario ONTraC -2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
yes no
otherprovinces
pe
rce
nt
ch
an
ge
RCC used 2003 vs 2002
• Reduction in allogeneic transfusion markedly exceeds the anticipated 5-10%• Historically, Ontario had the highest annual rate of increase in RCC use;• 2003, Ontario had lower increase (net decrease) in RCC use than other provinces; • ONTraC hospitals had lower increase in RCC use than non-ONTraC hospitals
.
7210
knee CABG AAA0
10
20
30
40
per
cen
t re
du
ctio
nProjected % reduction from baseline in allogeneicRCC use for province for the 3 targeted procedures
At 12 mos
At 18 mos RCC use 2003 vs 2002
Ontario ONTraC -2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
yes no
otherprovinces
pe
rce
nt
ch
an
ge
RCC used 2003 vs 2002
• Reduction in allogeneic transfusion markedly exceeds the anticipated 5-10%• Historically, Ontario had the highest annual rate of increase in RCC use;• 2003, Ontario had lower increase (net decrease) in RCC use than other provinces; • ONTraC hospitals had lower increase in RCC use than non-ONTraC hospitals
Fresh Component UseOntario Compared to the Rest of Canada
500,000
550,000
600,000
650,000
700,000
750,000
800,000
850,000
1999/2000 2000/2001 2001/2002 2002/2003 2003/2004
All Canada (except QC & ON) Ontario
Ontario Compared to Canada
73
Red Cells
24.0
26.0
28.0
30.0
32.0
34.0
36.0
1999/2000 2000/2001 2001/2002 2002/2003 2003/2004 2004/2005 2005/2006
Canada (except ON & QC) Ontario
Red Cells Issues - Ontario Compared to Rest of Canada (excl. QC)(per 1,000 population) 1999-2000 to 2005-2006
74
0
2
4
6
8
10
12
14
16
1 2 3
Allogeneic
No Tx
p<.05p<.001p<.01
5.445.332.25No Tx
11.6614.935.58Allogeneic
Rate of Infection (%)
CABGAAAKnee
Transfusion-induced immunomodulation: infection rate Infection defined by symptoms + pos culture
6
%
75
J Surg Research 2002;102:237-244
Prospective data from 6301 non-cardiac surgical procedures 1995-2000
Transfusion PRBCs > 4 units
Odds Ratio:Death 2.84 Infection 9.28
P<0.001 for both
767
baseline 12 months0
1
2
3
4
5
6
7
8
9no transfusionallogeneic transfusion
ALOS (mean + SEM) for no transfusion vs allogeneic transfusion
*For all comparisons of no transfusion vs allogeneic transfusion, P < 0.0001
knees AAA CABG knees AAA CABG
*
**
*
*
*
AL
OS
(da
ys)
IN MULTIVARIATE ANALYSIS, ALLOGENEIC TRANSFUSION WAS AN INDEPENDENT PREDICTOR FOR LOS
VARIABLES EVALUATED: Co-morbidities; Initial, pre-op, nadir & discharge hemoglobin levels; Postoperative infection; Age; Sex; Number of units of blood transfused; Any blood conservation measure (PAD, EPO, cell saver, controlled hypotension, fibrin glue, DDAVP, antifibrinolytics)
Average length of stay (ALOS; days) (mean SEM)
7
baseline 12 months0
1
2
3
4
5
6
7
8
9
no transfusionallogeneic transfusion
ALOS (mean + SEM) for no transfusion vs allogeneic transfusion
*For all comparisons of no transfusion vs allogeneic transfusion, P < 0.0001
knees AAA CABG knees AAA CABG
*
**
*
*
*
AL
OS
(da
ys
)
baseline 12 months0
2
4
6
8
10
12
14
16
no transfusionallogeneic transfusion
*For all comparisons of no transfusion vs allogeneic transfusion, P < 0.0001
knees AAA CABG knees AAA CABG
*
**
*
*
*
AL
OS
(da
ys
)
Average length of stay (ALOS; days) (mean ± SEM)
77
0
2
4
6
8
10
one knee
No transfusion Autologous Allogeneic
Average length of stay (ALOS; days) (mean + SEM)
AL
OS
(d
ay
s)
78
P < 0.0001
Pre-op Hb
Pre-op Hb (g/L)
Pre-op Hb Mean Pre-op Hb
Pre-op Hb versus number of units transfused
79
Compared to NO transfusion:
Knee CABG AAAEvery ↓ in pre-op Hb of 10 g/L increases chance of allogeneic transf by 1.839 (84%) 1.847
1.433Every ↓ in nadir Hb of 10 g/L increases chance of allogeneic transf by 4.31 (430%) 4.502
3.534
As age increases by 10 yrs, the odds of an allogeneic transfusion by 1.515 1.558 1.818As BSA decreases by -0.25, the odds of an allogeneic transfusion by 1.466 2.288 1.598Being female increases the odds of receiving allogeneic transfusion by 1.445 6.820 1.987
Having an allogeneic transfusion odds of postoperative infection by 2.653 2.681 1.950
Each additional allogeneic unit the chance of infection by a factor of 1.587 1.524 1.488
80
1.3381.79
2.395
3.205
1.524
2.323
3.54
5.394
1.312
1.721
2.258
2.963
1
2
3
4
5
6
Odds Ratio Compared to
having 0 Units
transfused
One Knee CABG AAA
# of Allogeneic Units Transfused
1
2
3-5
6+
1.102
1.214
1.338
1.475
1.109
1.23
1.364
1.513
1.074
1.153
1.239
1.331
1
1.2
1.4
1.6
1.8
2
Odds Ratio Compared to
having 0 units
Transfused
One Knee CABG AAA
# of Allogeneic Units Transfused
1
2
3-5
6+
Increased risk
of LOS per allogeneic units RCC transfused
Increased risk of
postoperative infection per allogeneic units RCC transfused
81
At 12 months, For Ontario, estimate for the 3 targeted procedures only:
• Red cell product (at $400/unit) 8,640,000
• Reduced LOS 5,300,000
• Reduced work in hospitals 650,000
Total savings per year: $14,950,000
• In addition: greater patient satisfaction and safety
Cost of program per year: $ 1,800,000
Expansion to other procedures & other conservation measures should result in even greater savings
82
DEMANDDEMAND SUPPLY
SUPPLY
What’s best for the What’s best for the blood supply?blood supply?
What’s best for the What’s best for the patient?patient?
83
V x=
Formula for “Scientific” Medical Formula for “Scientific” Medical OpinionOpinion
T4
AG
Volume of hot air
Academic rank (Professor =1 , Lecturer = 4)
Years from graduation
Distance from regular patient contact
J Isbister, SABM, 2005
84
Evidence Based Medicine
Minimal variation inclinical practice with people perpetuating
the mistakes of others
Clinical ExperienceRepeating one’s
own mistakes with increasing
confidence over time
Nothing is black and white, medicine ispracticed in the context of constant
uncertainty
CLINICAL DECISION MAKING
85
LawLaw
PoliticPoliticss
PerceptiPerceptionon
PracticPracticee
EvidenEvidencece
SciencSciencee
J Isbister
86
Thomas S. Kuhn 1922-1996
Relace transfusion with
• Blood conservation =• Bloodless medicine =• Bloodless surgery =• Blood management
87
Ott DA, Cooley DA. Cardiovascular surgery in Jehovah's Witnesses. Report of 542 operations without blood transfusion. JAMA 238:1256-8, 1977.
Jehovah's Witnesses who require operation represent a challenge to the physician because of the patients' refusal to accept blood transfusion. We report a 20-year experience with a consecutive series of 542 Jehovah's Witness patients ranging in age from 1 day to 89 years who underwent operation. Early mortality (within 30 days after operation) was 9.4%. In 362 patients requiring temporary cardiopulmonary bypass, early mortality was 10.7%. Mortality was 13.5% among 126 patients who had single- or double-valve replacement. The only deaths among patients who had aortic valve replacement or repair of a ventricular septal defect occurred in those who had some serious complication before operation. Preoperative or postoperative anemia was a contributing factor in 12 deaths, and loss of blood was the direct cause of three deaths. Cardiovascular operations can be performed safely without blood transfusion.
Bloodless Bloodless SurgerySurgery
88
89
• Blood transfusion is risk factor for:– Mortality– ICU admission– ICU length of stay– Hospital length of stay
90
Why “bloodless medicine”…?
There are many bloodless medicine programs …and the number is growing. Even in remote areas of Siberia, physicians and patients know about bloodless medicine.
If one types “bloodless medicine” into an internet search engine, > 12,000 hits are obtained.…
[from T Kickler, Johns Hopkins, Transfusion 43:550, May 2003]
91
Bloodless medicine (or blood conservation)Requires coordination of services across a variety of departments….cooperation between outpatient scheduling, surgical and anesthesia physicians and their clinic personnel, operating room scheduling, intensivists and hematologists to get the patient prepared, …the billing office….
This is in contrast to a transfusion, which can usually be accomplished with one phone call….
[from T Kickler, Johns Hopkins, Transfusion 43:550, May 2003]
92
Some institutions market their bloodless medicine programs by pointing out the complications and adverse effects of allogeneic transfusion, as a way to lower hospital expenses or length of hospital admissions.
May be so, but careful outcomes research needed before making this the only argument to establish bloodless medicine program.
The strongest argument for having a bloodless medicine program is to respect the rights of patients…. based on the ethical value of autonomy or self-determination, and medical institutions have a responsibility to respond to this need.
A plethora of new techniques and therapies are available …and their relative merits, alone and in combination, still needs to be investigated, but it is becoming standard of practice.
93
3 year renewable contract signed; to 2009
5 new coordinators; 3 new sites
New targeted procedures
94
Radical prostatectomy
0
5
10
15
20
25
30
35
40p
erce
nt
rece
ivin
g a
llog
enei
c tr
ansf
usi
on Individual sites
Aggr
mean
95
One knee: mean nadir Hb
60
65
70
75
80
85
90
Hb
(g
/L)
CABG: mean nadir Hb
60
65
70
75
80
85
90
baseline12 months18 months
Hb
(g
/L)
• Nadir hemoglobins higher for autologous than for allogeneic transfusions• Progressive reduction in hemoglobin level trigger for transfusions• Trigger hemoglobin higher in knee surgery than in CABG !!
Nadir hemoglobin levels as surrogate measure of transfusion trigger
9
Radical prostatectomy:Non-autologous 83.29Autologous 89.47
96
Radical prostatectomy(N=863)
0
10
20
30
40
50
pe
rce
nt
20% of Pts had autologous blood collected, of whom 47% received their autologous blood; only 3.47% also received allogeneic blood.
42% of autologous units collected were transfused.
97
PatientPatientBlood Blood
ManagementManagement
Opinion Opinion LeaderLeader
SurgeonSurgeon
Anesthesi-Anesthesi-ologistologist
HematologistHematologistCooordinatorCooordinator
BureaucratBureaucratICU &ICU &WardsWards
98
Allogeneic blood transfusion should only be used as therapy when there is evidence for potential benefit, there are no alternatives, a quality product is available and the risks are appropriately considered and balanced against the benefits.
The best transfusion is the transfusion not given!
☺Thank you
99
100
percent of patients undergoing PAD
knee CABG AAA0
5
10
15
20 baseline12 months18 months
per
cen
t o
f p
atie
nts
Procedures employed:
• Increase in pre-operative autologous donation in CABG & AAA patients• Progressive increase in use of erythropoietin after first year
11
0
10
20
30
40
50
nu
mb
er
pa
tie
nts
pe
r m
on
th
Overall EPO use per month
PAD EPO
101
Procedures Utilized (% of patients)
0%
10%
20%
30%
40%
50%
60%
70%
OneKnee
AAA CABG OneKnee
AAA CABG
Cell Saver Antifibrinolytics
Procedure
Utiliz
ed
Baseline
12 Months
Procedures Utilized
0%
2%
4%
6%
8%
10%
OneKnee
AAA CABG OneKnee
AAA CABG OneKnee
AAA CABG
Fibrin Glue Hypotension DDAVP
Procedure
% U
tiliz
ed
Baseline
12 Months
Cell saver antifibrinolytics
Fibrin glue hypotension DDAVP
Limited use of other procedures; specific for type of surgery
Other blood conservation procedures (% of patients)
13
102
Miscellaneous slides
103
Pharmacologic agents: costs
» Cost per dose Cost per course
• Eprex 588 2,350• Darbopoietin 132 530• Amicar 18 46• Aprotinin 540 1,000• DDAVP 144• Tranexamic acid 73• rFVIIa 7,056 (4.8
mg)
Jabbour
104
Transfusion triggerRestrictive vs Liberal
105
106
107
108
Consider: PAD EPO cell saver
Hb > 130 g/L N/A
Hb >100 - <130 g/L N/A
Surgery 2 to 4 weeks away N/A
>10% likely to require transfusion Anticipated blood loss (units) 1-2 1-5 >1;
>20% BV
Need for Fe supplement
Not within 72 h of surgery
109
Factors to consider in the surgical transfusion decision
Clinical history
Cardiopulmonary disease
Existing coagulopathy
Anemia
Trauma classification (mechanism of injury)
Medications
Antiplatelet drugs; Anticoagulants
Clinical symptoms
Dyspnea on exertion; Angina
Hemoglobin/hematocrit level
Oxygen delivery/consumption
Surgical procedure (elective vs emergency; laparoscopic vs open)
Estimated blood loss
Jehovah’s Witness
110
Independent predictors for transfusion:
Preoperative factors: Red blood cell mass Type of operation Urgency of operation Number of diseased vessels Serum creatinine > 1.3 mg/dL Preoperative prothrombin time
Postoperative factors: Cardiopulmonary bypass time Three or fewer bypass grafts Lesser volume of ANH removed Total crystalloid > 2500 ml Moskowitz et al
111
24,509 consecutive adult surgical patients; 14 procedures (not neuro or cardiac)
• Type of procedure
• Age
• Sex
• Emergency surgery
• Preoperative autologous donation
• Preoperative hemoglobin level
Identifying patients for blood conservation strategies. Van Klei et al, Br J Surg 89:1176, 2002
Identifying patients for blood conservation strategies
112
Preoperative autologous donation (PAD)
Consider when:
Preoperative hemoglobin >130 g/L> 10% of patients undergoing procedure
require transfusion Elective surgery scheduled 2 to 4 weeks away
Patient on iron supplement Not within 72 h of surgery
no severe cardiovascular or hemodynamic problems
113
Autologous blood donation
Advantages Disadvantages
Prevents transfusion-transmitted disease No effect on risk of bacterial contamination
Prevents red cell alloimmunization No effect on risk of ABO incompatibility error
Supplements the blood supply Costs more than allogeneic blood?
Provides compatible blood for pts with alloabs Wastes blood not transfused
Prevents some adverse reactions Possible adverse reactions from donation
Reduces likelihood of allogeneic transfusion May subject patient to preoperative anemia
114
Autologous donation deferral
• evidence of infection or bacteremia
• severe aortic stenosis
• unstable angina
• myocardial infarction or cerebrovascular accident in past 6 months
• high grade left main coronary artery disease
• cyanotic heart disease
• active seizure disorder
• uncontrolled hypertension
Br J Anaesth 78:768, 1997
115
PAD
observational
42 studies
RR 0.31
[Carless et al
Transf Med 14:123, 2004]
116
PAD
randomized
8 studies
RR 0.37
117
Autologous Donation:
In contrast to autologous blood donation under standard
conditions, in “aggressive” autologous blood phlebotomy
(twice weekly for 3 weeks beginning 25-35 days before surgery)
endogenous erythropoietin levels do increase.*
Can be further stimulated by exogenous erythropoietin.**
* Goodnough et al: J Lab Clin Med 236:57, 1995
**Goodnough et al: N Engl J Med 336:933, 1997
118
Erythropoietin
Consider when:
Anticipated loss of two to five units Preoperative hemoglobin >100 to < 130 g/L
Elective surgery scheduled 2 to 4 weeks away Patient on iron supplement
119
Different Formulations of Recombinant Erythropoietin
Estimated total number of cases of PRCA is about 250Possibly related to formulation and increased incidence with sq administrationNever seen if EPO is administered IVSince 1998- 1.7/10,000 cases in France, 0.26/10,000 cases in Germany
120
121
Percent patients transfused with allogeneic blood
0
10
20
30
40
50
60p
erc
en
tCABG:
.
.
.
.
.
122
Cell Salvage
Consider when:
Blood loss likely >20% of blood volume > 10% of patients undergoing procedure
require transfusion Mean transfusion requirement exceeds one unit
123
ANH
Consider when:
Blood loss likely >20% of blood volume Preoperative hemoglobin >100 g/L Absence of severe cardiac disease
124
Before planned surgery:
• Assessment at preadmission clinic
• Correcting treatable anemia
• Stopping anticoagulants and antiplatelet drugs,
if safe to do so
• Erythropoietin and /or iron
• Pre-donation of blood, with hematinics + erythropoietin
• Minimizing blood taken for laboratory samples
125
During surgery:
• Losing less blood through optimal surgical & anesthetic technique
• Keeping patient warm
• Using measured hematocrit or blood loss as guide to red cell replacement
• Using rapid hemostasis testing to guide blood component replacement
• Antifibrinolytics to reduce bleeding in selected cases
• Intraoperative cell salvage
126
After surgery:
• Postoperative cell salvage
• Using a protocol to trigger re-exploration at a specified level of blood loss
• Use of a protocol to guide when hemoglobin should be checked
• Use of a protocol stating blood transfusion thersholds and targets
• Minimizing blood taken for laboratory samples
127
At surgery:
Meticulous dissection:
• Develop avascular planes
• Stop all small bleeders as encountered
Reduction of regional vascular pressure
• Appropriate patient position
• Blood inflow control
• Limb exsanguination & proximal tourniquet
Prevention of hypothermia
Optimal use of cell salvage-
128
“Haemostatic” dissecting instruments:
mechanism disadvantages applications
Monopolar diathermy heat transmission collateral thermal damage; most proceduresinterferes with pacemakers; ignition of flammable fluid/gas
Bipolar diathermy heat cannot “cut” tissues; where need ignition flammable gas/fluid precise dissection
Argon beam heat collateral thermal damage; hepatobiliaryinterferes with pacemakers; surgeryignition of flammable gas/fluid
Laser (e.g. Nd-YAG, CO2) heat as above according to laser type
Ultrasound dissector mechanical cost solid organ disruption; some heat surgery
Water-jet dissectormechanical cost solid organ surg
129
Key points:
surgical technique is most important determinant of blood loss
simple physical methods result in significant reduction in blood loss
minimally invasive surgery can contribute to blood conservation
modern ‘haemostatic’ surgical instruments can contribute to bloodless dissection, especially with solid organ surgery
topical haemostatic agents, particularly fibrin sealants, help when bleeding not controlled by more
straightforward means
130
Pharmacologics:
• High dose aprotinin reduces red cell and component use in cardiac, hepatic transplant and major orthopedic (but not vascular) surgery
• Tranexamic acid inconsistent in reduction of red cells and no effect on component use
• Tranexamic acid no proven benefit in patients taking antiplatelet drugs
• EACA does not reduce allogeneic transfusion
• DDAVP after cardiac surgery may be useful in proven platelet dysfunction
• rFactor VIIa: await evidence from randomized placebo-controlled studies
131
Potential difficulties:
• Clinical/diagnostic criteria not detailed enough
• Clinical information often missing/difficult to interpret
• Donor samples difficult to retrieve; donor recall delayed
• Shipping of samples: time, conditions
• Crossmatch samples availability rare
• Sensitivity of tests:
• inherent
• panel antigen coverage
• false positives and negatives
• technique specific
132
Factors to consider in the surgical transfusion decision
Clinical history
Cardiopulmonary disease
Existing coagulopathy
Anemia
Trauma classification (mechanism of injury)
Medications
Antiplatelet drugs; Anticoagulants
Clinical symptoms
Dyspnea on exertion; Angina
Hemoglobin/hematocrit level
Oxygen delivery/consumption
Surgical procedure (elective vs emergency; laparoscopic vs open)
Estimated blood loss
Jehovah’s Witness
133
24,509 consecutive adult surgical patients; 14 procedures (not neuro or cardiac)
• Type of procedure
• Age
• Sex
• Emergency surgery
• Preoperative autologous donation
• Preoperative hemoglobin level
Identifying patients for blood conservation strategies. Van Klei et al, Br J Surg 89:1176, 2002
Identifying patients for blood conservation strategies
134
K Sazama, Vox Sang 92:95-102, 2007.
135K Sazama, Vox Sang 92:95-102, 2007.
136
137Van der Linden P, Dierick A: Vox Sang 92:103-112, 2007.
138Van der Linden P, Dierick A: Vox Sang 92:103-112, 2007.
139Van der Linden P, Dierick A: Vox Sang 92:103-112, 2007.
140
141
142
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